We report that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta spike mutation P681R plays a key role in the Alpha-to-Delta variant replacement during the coronavirus disease 2019 (COVID-19) pandemic. Delta SARS-CoV-2 efficiently outcompetes the Alpha variant in human lung epithelial cells and primary human airway tissues. The Delta spike mutation P681R is located at a furin cleavage site that separates the spike 1 (S1) and S2 subunits. Reverting the P681R mutation to wild-type P681 significantly reduces the replication of the Delta variant to a level lower than the Alpha variant. Mechanistically, the Delta P681R mutation enhances the cleavage of the full-length spike to S1 and S2, which could improve cell-surface-mediated virus entry. In contrast, the Alpha spike also has a mutation at the same amino acid (P681H), but the cleavage of the Alpha spike is reduced compared with the Delta spike. Our results suggest P681R as a key mutation in enhancing Delta-variant replication via increased S1/S2 cleavage.

我们报告说，严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) Delta 尖峰突变 P681R 在 2019 年冠状病毒病 (COVID-19) 大流行期间的 Alpha 到 Delta 变体替换中发挥着关键作用。在人肺上皮细胞和人原代气道组织中，Delta SARS-CoV-2 有效地击败了 Alpha 变体。 Delta 刺突突变 P681R 位于分隔刺突 1 (S1) 和 S2 亚基的弗林蛋白酶切割位点。将 P681R 突变恢复为野生型 P681 显着减少了 Delta 变体的复制，使其水平低于 Alpha 变体。从机制上讲，Delta P681R 突变增强了全长刺突对 S1 和 S2 的裂解，这可以改善细胞表面介导的病毒进入。相比之下，Alpha刺突在相同氨基酸（P681H）处也有突变，但与Delta刺突相比，Alpha刺突的裂解减少。我们的结果表明 P681R 是通过增加 S1/S2 裂解来增强 Delta 变体复制的关键突变。